Psychopharmacology (1992) 106: S 134~S136

Psychopharmacology © Springer-Verlag 1992

Use of moclobemide in children with attention deficit hyperactivity disorder G.E. Trott, H.J. Friese, M. Menzel, and G. Nissen Hospital for Child and Adolescent Psychiatry, University of Wfirzburg, F/ichsleinstrasse 15, W-8700 Wfirzburg, Federal Republic of Germany

Abstract. A monoamine oxidase hypothesis for the cause of attention deficit hyperactivity disorder has recently been established (Shekim et al. 1986). To test this, moclobemide, a new and reversible inhibitor of monoamine oxidase-A, was administered to 12 children between the ages of 6 and 13 years, diagnosed as attention deficit hyperactive according to D S M I I I - R , in a 4-week study. All had previously discontinued treatment with methylphenidate due to side-effects. A 40% improvement in parental assessment of children's behaviour occurred among those who received moclobemide as outpatients, and a 31% improvement among the five in-patients. There was a general increase in concentration and attention span at the end of the trial, but m o o d changes and explosive behaviour continued to be present at a low level. Brain mapping after moclobemide treatment showed an overall reduction in frontal lobe delta activity. Moclobemide was well tolerated by these patients, although two complained of mild gastrointestinal disturbances during the first week of therapy.

Key words: Moclobemide

Monoamine oxidase inhibitor - Hyperkinetic syndrome - Attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder ( A D H D ) occurs in between 3 and 10% of children of school age and is one of the most c o m m o n childhood and adolescent psychiatric conditions. It is characterised by strong behavioural abnormalities, but differs from a behavioural lack of adaptation by the child to a change in external and cultural conditions. The initiation of pharmacotherapy to treat A D H D occurred when amphetamines were first prescribed by Bradley in 1937. Methylphenidate remains a current treatment, although side-effects may restrict its use. In 1980, Young et al, demonstrated an age-related decrease in monoamine oxidase (MAO) in the thromOffprint requests to." G.E. Trott

bocytes of normal children which did not occur in children with A D H D . Tests carried out by Zametkin and co-workers (1985) to further examine the M A O basis of A D H D showed that while the classic M A O - A inhibitor, clorgyline and the combined M A O - A and M A O - B inhibitor, tranylcypromine improved the condition of children with A D H D , the adminstration of deprenyl, an inhibitor of M A O B alone, had little effect. We have performed a 4-week study in children with A D H D to examine the effects of moclobemide, a new, specific, and reversible inhibitor of M A O - A .

Materials and methods A 4-week study was performed at the University of Wurzburg to examine the effects of moclobemide (F. Hoffmann-La Roche, Basle), a reversible MAO-A inhibitor, in children who fulfilled the criteria for attention deficit hyperactivity disorder according to DSM III-R. Consent for the study was obtained from the ethics committee of the University. Children with a history of epilepsy, conduct disorder or allergies were excluded from the trial, as were those with measured IQs of less than 70 (WISC-R). Twelve children of normal intelligence, between the ages of 6.6 and 12.9 years, were included in the trial; 11 male and 1 female. Seven were treated as outpatients and five as inpatients. All had previously been treated with methylphenidate for 4~ 18 weeks prior to the trial and had responded well. In each case, however, methylphenidate had been discontinued due to undesirable side effects: sleeping problems (six cases), depression (four cases) and therapeutic inefficacy(two cases). No child had received drug therapy during the 10 days immediately prior to the trial. Treatment schedules'. Following a 3-day placebo phase, moclobemide was administered to all children at a dose of 100 mg (range 2.3-5 mg/kg body weight). All children received moclobemide twice daily, at 7 a.m. and 1 p.m. Dose increments of 50 mg occurred on days 8 and 14, up to a final total dose of 200 mg moclobemide daily. Observation and measurements. Medical, neurological and laborat-

ory examinations, including blood chemistry analysis (white and red blood cell counts, GOT, GPT, creatinine, gamma-GT, bilirubin), ECG and EEG were performed regularly throughout the trial. Pharmaco-EEG analysis was recorded by means of brain mapping (Cateem system) at the beginning and the end of the treatment period.

S135 The therapeutic effects of moclobemide were evaluated at the beginning of the trial, following the placebo phase, and then at weekly intervals. Records of dosage were kept throughout the trial and symptoms which emerged during treatment were logged. Behavioural levels were measured subjectively at the end of the 4-week period using the Conners scale, and both parent and teacher questionnaires were issued. Clinical global impression (CGI) assessment was also carried out at the end of the trial. Among the objective neuropsychological tests of learning and memory performed were the d-2 test and the differential performance test for children of elementary school age (DLGT). In addition, a computer-based Cognitrone diagnosis was performed. Motor activity was measured using an Actigraph (Porrino et al. 1983), and talking behaviour monitored with a Logoport (Kruger 1989).

Results Eleven patients completed the 4-week treatment course. One child was removed from the trial at the request of the parents because of limited clinical improvement. Moclobemide was well tolerated by all patients. Only two children complained of vague gastrointestinal disturbances during the first week of the trial. The E C G revealed no pathological abnormalities in the children either before or during the treatment period. N o significant changes in blood chemistry or E E G measurements occurred. Among the seven outpatients in the trial, there was an improvement o f approximately 40% in parental assessment of the child's behaviour as measured on the abbreviated Conners scale (Conners 1969): ratings decreased from an average of 19.1 on trial entry to 11.6 at the end o f the 4-week period. For the five children who were treated as inpatients, behavioural improvement was approximately 31% (ratings=44.5 at day zero and 30.6 at day 28). Following treatment with moclobemide the children were rated less whiny and more tolerant of frustration by their parents (Fig. 1). A reduction of over 50 % in restlessness occurred, and a 47 % reduction in disturbing behaviour against other children, impulsive behaviour and unrest. The length of attention span increased by 30% during the course of the treatment, although the incidence of explosive behaviour and slight distractability increased. Overall, there was a low frequency of rapid and pronounced m o o d changes. During the course of moclobemide treatment, the majority of children demonstrated an increase in concentration levels. In the concentration check test, scores rose from 30.6 to 56 (an improvement of 82%) and then to 67 by the end of the trial (117% improvement). However, in one patient with severe emotional and family problems, a deterioration in test performance occurred during the trial period. Results from a computer-based assessment of attentiveness and memory function showed an overall decrease in both discrimination time and recognition time (Fig. 2). The number of test errors made by the children was reduced by 41% after treatment with moclobemide. Nine of the patients underwent brain-mapping by Cateem scan for a period of 15 min prior to trial entry. Maximal delta activity was found above the frontal sec-

Rating scale 0-3

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Fig. 1. Single item analysis of parental assessment of behaviour, before and after moclobemide treatment (n = 7), as measured ,on the abbreviated Conner's rating scale (scores 1-3). (I) Hyperactive; (2) impulsive; (3) disturbs other children; (4) short attention; (5) permanently fidgety; (6) easily distracted; (7) easily frustrated; (8) easily and often weeping; (9) rapid change of mood; (10) explosive behaviour. [] Day 0; • day 28 250"

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Fig. 2. Computer-based assessment o f c o n c e n t r a t i o n and m e m o r y

function before and after moclobemide treatment using Cog-

nitrone-PC (n = 7). [] Discrimination time; [] discrimination faults; [] memory time; • memory faults in % of relative delta-activity 200

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0Patient 1 Patient 2 Patient 3

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Relative Delta Activity

Fig. 3. Cumulative delta activity in the frontal lobes of patients (n = 6) before and after moclobemide treatment (Cateem scanning). [] Day 0; • day 28 tors of the brain in eight of these patients, and an average frontal total delta activity of 149% was measured. Six of these patients received a follow-up scan at the end o f the treatment period. The relative delta activity in three of the six was reduced by an average of 35% (Fig. 3)

S136 Discussion

Conclusion

During the 4-week treatment period, the children's psychological status, as determined by CGI testing, improved from "seriously ill" to "moderately ill". A clear improvement in symptoms was noted following the administration of moclobemide. Moclobemide proved generally effective in the treatment of A D H D , with a very low incidence of side effects. However, three patients did not show clinical improvement at CGI assessment. These included both patients who had previously failed to respond to therapy with methylphenidate, while the third patient was a child of subnormal intelligence resulting from foetal alcohol syndrome. Although the attention span of these children was improved following moclobemide treatment, rapid mood changes and explosive behaviour were observed at low levels. Thus it is likely that the therapeutic activity of moclobemide in A D H D patients is not mediated by its antidepressant effect. Moclobemide appeared to be most effective when used at a dose of 150 mg daily. For two patients, an increase in dose brought about only slightly improved therapeutic results, but three patients did show an increased clinical response when moclobemide 200 mg was administered. Typically, the brain maps of children with A D H D showed a focus of delta activity located in the frontal lobe which may relate to a decrease in glucose metabolism in this area (Zametkin 1990). Delta activity was significantly reduced in children treated with moclobemide and further mapping revealed that the activity was restricted to the occipital areas.

Analysis of the results from this study shows that moclobemide is an effective and well tolerated treatment for attention deficit hyperactivity disorder. None of the sideeffects, including dysphoria and insomnia, which led to the discontinuation of initial methylphenidate treatment in these children recurred during moclobemide usage. Parent and teacher ratings of behavoural improvement, as well as neuropsychological testing, confirmed the effectiveness of moclobemide in this disorder. References Bradley C (1937) The behaviour of children receiving benzedrine. Am J Psychiatry 94:577-585 Conners CK (1969) The teachers' rating scale for use in drug studies with children. Am J Psychiatry 126:884-888 Kruger HP (1989) Speech chronemics - a hidden dimension of speech. Theoretical background, measurement and clinical validity. Pharmacopsychiatry 22[suppl]: 5-12 Porrino L., Rapoport J, Behar D, Ismond D, Bunney W (1983) A naturalistic assessment of the motor activity of hyperactive boys. Arch Gen Psychiatry 40:681-687 Shekim WO, Bylund DB, Alexon J (1986) Platelet MAO and measures of attention and impulsivity in boys with attention deficit disorder and hyperactivity. Psychiatry Res 18:179-188 Young JG, Cohen D J, Waldo MD, Feiz R, Roth JA (1980) Platelet monoamine oxidase activity in children and adolescents with psychiatric disorders. Schizophren Bull 6[2]:324-333 Zametkin A, Rapoport JL, Murphy DL, Linnoila M, Ismond D (1985) Treatment of hyperactive children with monoamine oxidase inhibitors. Arch Gen Psychiatry 42110]:962-966 Zametkin AJ, Nordahl TE, Gross M, King AC, Semple WE, Ramsey J, Hamburger S, Cohen RM (1990) Cerebral glucose metabolism in adults with hyperactivity of childhood onset. N Engl J Med 323:1361-1366